Cojocaru: In Silico Biomolecular Structure and Dynamics

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We use computational approaches to understand the structure and dynamics of biomolecules at or near atomic resolution, with a special focus on biomolecular recognition. In particular, we are interested in how a special class of proteins known as transcription factors explore DNA to recognize their binding sites, a process crucial for establishing gene regulation programs that confer a specific identity to a given cell.

Figure 1. The Oct4-Sox2 (left) and Oct4-Sox17 (right) complexes bound to their DNA recognition motifs. The two DNA binding domains of Oct4 are in red and mauve and the linker between them is in green. Sox2 is in dark blue and Sox17 in brown. DNA is in yellow. For artwork, two flanking nucleosomes are shown with the core histones in green. The phase-contrast illustrations of the embryonic stem cells (lower left) and the primitive endoderm cells (lower right) were provided by Kenjiro Adachi (Max Planck Institute Münster).

DNA recognition in nucleosome free regions

Transcription factors are proteins that recognize specific DNA elements in the genome to establish gene regulation programs. Many of them are involved in defining the identity of the cell. Moreover, some transcription factors can be induced to change the fate of a cell. For example, four transcription factors are sufficient to convert a somatic cell to a pluripotent cell, very closely resembling an embryonic stem cell. This process, known as cellular reprogramming has important implications for regenerative medical applications. Among these four factors, Oct4, a member of the POU family binds cooperatively with different members of the Sox family to composite motifs with varying spacers between the individual binding sites. In recent years, we have elucidated the structural features and dynamics that modulate the cooperativity of Oct4 with Sox2 in pluripotent cells and with Sox17 in primitive endoderm cells (Figure 1).  Based on these findings, we predicted and validated mutations that modify the function of the Sox factors. Currently, we are aiming to understand different mechanisms by which transcription factors use multiple DNA binding domains and DNA binding cooperativity to recognize DNA to establish multiple layers of specificity required for the tight regulation of gene expression.

Group leader

Vlad Cojocaru

Vlad Cojocaru has a long time interest in understanding how the structure and dynamics modulate the function of biomolecules in cells. In particular, he is fascinated by a class of proteins known as transcription factors, some of which have the unique capacity of driving cell fate transitions. His research is aimed at understanding how these factor recognize their binding sites on DNA, a process that is essential for their function. For this, he uses computational methods to simulate the dynamics of molecular systems at or near atomic resolution. In recent years, these methods, grouped as “molecular dynamics simulations”, have been proven to be very accurate in describing the dynamics of biological macromolecules. Vlad’s ultimate goal is to understand how transcription factors explore and modify the structure of DNA in different chromatin contexts (e.g. presence and absence of nucleosomes) and to engineer transcription factors with modified behavior that can be used to drive, optimize, or inhibit cell fate transitions.

Group members

Vlad Cojocaru

Principal Investigator